Tag Archive for 'genetics'

De novo mutations and Autism redux

In articles published online by Nature, Professors Stephan Sanders and colleagues and Brian J. O’Roak his colleagues reported additional evidence that rare mutations contribute to risk for Autism. By analyzing genetic material from parents who had children with Autism, the researchers were able to focus on differences in specific genes, what changed from one generation to the next. One team, working in the research lab of Professor Matthew State at Yale University, found strikingly unusual matches for a specific mutation at SCN2A. The other team, under the direction of Professor Evan Eichler at the University of Washington, found several candidates (including SCN1A) and a strong (4 to 1) relationship for older fathers.
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Little sibs of children with ASD have greater risk of Autism

In Pediatrics Professor Sally Ozonoff and her colleagues of the Baby Siblings Research Consortium have reported data indicating a substantially higher risk for Autism among siblings than had been previously found. Based on data from studies in the 1980s, estimates of the risk of Autism in a child given that an older sibling had Autism were in the range of 3 to 5%, the Consortium found that the risk may be as great as four times higher than that, perhaps as high as 20%.

The researchers in the Consortium used very careful methods in which they found 664 later-born, biological siblings of a child with Autism when that younger sibling was, on average, about 8 months old. They followed the development of the siblings and assessed whether they had the symptoms of Autism when they were 36 months old. They found almost 19% had scores above the cut-off for Autism. The risk for Autism was even greater for boys and when more than one older sibling had Autism.
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Chromosomes linked to Autism

In a letter to Nature, Lauren Weiss, Dan Arking, the Gene Discovery Project of Johns Hopkins, and the Autism Consortium report that they have analyzed multiple data sets and identified potential loci on human genes for susceptibility for Autism. They found possible linkages on four chromosomes (5p15, 6q27, and 20p13) and, coupled with other data, the single nucleotide polymorphism on 5p15 pointed to SEMA5A as an important location for additional study. These results may lead to a means of screening; if rare variations can be identified reliably, they would permit families to seek intervention very early in the lives of affected individuals, thus greatly increasing the chances of improved outcomes.

Although autism is a highly heritable neurodevelopmental disorder, attempts to identify specific susceptibility genes have thus far met with limited success1. Genome-wide association studies using half a million or more markers, particularly those with very large sample sizes achieved through meta-analysis, have shown great success in mapping genes for other complex genetic traits. Consequently, we initiated a linkage and association mapping study using half a million genome-wide single nucleotide polymorphisms (SNPs) in a common set of 1,031 multiplex autism families (1,553 affected offspring). We identified regions of suggestive and significant linkage on chromosomes 6q27 and 20p13, respectively. Initial analysis did not yield genome-wide significant associations; however, genotyping of top hits in additional families revealed an SNP on chromosome 5p15 (between SEMA5A and TAS2R1) that was significantly associated with autism (P = 2 10-7). We also demonstrated that expression of SEMA5A is reduced in brains from autistic patients, further implicating SEMA5A as an autism susceptibility gene. The linkage regions reported here provide targets for rare variation screening whereas the discovery of a single novel association demonstrates the action of common variants.

Link to the abstract.

Possible balancer of neural excitation-inhibition?

Neurons in the central nervous system communicate with each other chemically through neural synapses. Neurons receive excitatory input from glutamatergic neurons and inhibitory input from GABA-releasing (GABAergic) interneurons. Some hypotheses about Autism are predicated on the possibility that there is an imbalance between the excitatory and inhibitory neural activity, perhaps especially in the so-called mirror neurons. Reporting in Nature, Yingxi Lin and fellow scientistics working in Michael Greenberg’s group at Harvard University have discovered a gene—Npas4—that may regulate the balance between excessive and insufficient excitation of synapses.
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Schizophrenia geneses

I guess one can read geneses as a typographical variant on genes or, as I intended, as the plural of genesis. Using it the latter way: Emerging evidence makes it appear even more unlikely than ever that researchers will be able to identify a relative few genes—let alone the or one gene—for schizophrenia. Writing under the headline “Gene-Hunters Find Hope and Hurdles in Schizophrenia Studies,” the noted science journalist Nicholas Wade published an article summarizing research that points to the conclusion that there may be many different genetic bases for schizophrenia.

Two groups of researchers hunting for schizophrenia genes on a larger scale than ever before have found new genetic variants that point toward a different understanding of the disease.
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The variants discovered by the two groups, one led by Dr. Kari Stefansson of Decode Genetics in Iceland and the other by Dr. Pamela Sklar of the Massachusetts General Hospital, are all rare. They substantially increase the risk of schizophrenia in those affected but account for a tiny fraction of the total number of cases.

This finding, coupled with the general lack of success so far in finding common variants for schizophrenia, raises the possibility that the genetic component of the disease is due to a very large number of variants, each of which is very rare, rather than to a handful of common variants.

This is an article well worth reading. Link to Mr. Wade’s arctile.

More de novo findings

Professor Lauren Weiss and colleagues form the Autism Consortium published a paper in the prestigious New England Journal of Medicine today that provides further and stronger evidence about genetic problems underlying Autism. They have identified changes in genetic structure that appear in a small number of children but not in those children’s parents.
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